Normal development of the human cerebral cortex is essential for cognitive function, and is disrupted in human neurological disorders such as mental retardation and epilepsy. Positional cloning efforts by our lab and others have identified several genes required for normal neuronal migration, including DCX, FLNA, ARFGEF2, Reelin, Dab1 and others. Since many of the mechanisms involved in axon outgrowth and neuronal migration are shared, some of these genes also have effects on axon outgrowth. Many of these genes encode cytoplasmic proteins that exert their effects via interactions with signaling pathways that are not yet well defined. The overall goal of this proposal is to analyze the role of the Reelin/Dab1 pathway, and of doublecortin (Dcx) and the doublecortin-like kinase (Dclk) in neuronal migration and axon outgrowth. These two pathways appear to converge on the control of microtubules and the regulation of process outgrowth in neurons. Specific aim 1 will analyze the role of the Reelin/Dab1 pathway in control of the leading process of migrating neurons. Specific aim 2 will analyze the role of Dclk in activity-related axon outgrowth and normal synaptic remodeling. Specific aim 3 will analyze the interacting roles of Dcx and Dclk in controlling the normal migration of neurons to the cerebral cortex, and the normal outgrowth and targeting of cortical axons: We hope that this work will not only improve out understanding of the normal role of these genes in cortical development but may also identify additional candidate genes for other human developmental disorders.